Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics

ABSTRACT

Thus, the present invention provides compounds of formula (I) The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a neurological disorder. The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain or migraine

FIELD OF THE INVENTION

The present invention relates to novel prodrug forms of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid, to pharmaceutical compositions containing the prodrug forms, andto methods of using the prodrug forms.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,670,516 discloses that certain decahydroisoquinolinederivatives are AMPA receptor antagonists, and as such are useful in thetreatment of many different conditions, including pain and migraine. Inaddition, WO 01/02367 A3, published Jan. 11, 2001, discloses diesterprodrug forms of the selective GluR₅ antagonist3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid.

It is an object of the present invention to provide monoesters of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid which provide improved bioavailability of the parent monoacid in apatient. In addition, it is an object of the present invention toprovide monoesters of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid which are substantially converted to the parent monoacid in thepatient.

SUMMARY OF THE INVENTION

It has now been discovered that the novel monoesters of the monoacid,(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid provide significantly improved bioavailability of the monoacid ascompared to that provided by administration of the monoacid itself. Inaddition, the monoesters are substantially converted to the monoacid inthe patient. The monoacid is disclosed in U.S. Pat. No. 5,670,516,issued Sep. 23, 1997.

Thus, the present invention provides compounds of formula I:

wherein R represents C₁-C₂₀ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkyl-aryl,C₁-C₆ alkyl-(C₃-C₁₀)cycloalkyl, C₁-C₆ alkyl-N,N—C₁-C₆ dialkylamine,C₁-C₆ alkyl-pyrrolidine, C₁-C₆ alkyl-piperidine, C₁-C₆ alkyl-morpholineor a pharmaceutically acceptable salt thereof.

The present invention further provides a method of antagonizing the AMPAor GluR₅ receptor, which comprises administering to a patient aneffective amount of a compound of formula I.

In addition, the present invention provides a method for the treatmentof a neurological disorder, which comprises administering to a patientin need thereof an effective amount of a compound of formula I.

The present invention further provides a method for the treatment ofpain or migraine, which comprises administering to a patient in needthereof an effective amount of a compound of formula I.

The present invention further provides the use of a compound of formulaI for the manufacture of a medicament for the treatment of aneurological disorder.

The present invention further provides the use of a compound of formulaI for the manufacture of a medicament for the treatment of pain ormigraine.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “prodrug” refers to a monoester derivative of acarboxylic acid functional drug, which derivative, when administered toa patient is converted into the monoacid (drug). The enzymatic and/orchemical hydrolytic cleavage of the compounds of the present inventionoccurs in such a manner that the parent monocarboxylic acid (drug) isreleased.

As used herein the term “Compound A” refers to(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid.

As used herein the term “Compound B” refers to6-[2-(2H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidethyl ester.

As used herein the term “Compound C” refers to6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid2-ethyl-butyl ester.

As used herein the term “Compound D” refers to6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidisobutyl ester.

As used herein the term “Compound E” refers to6-[2-(2H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid3-methyl-butyl ester.

As used herein the term “Compound F” refers to6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic aciddecyl ester.

As used herein the term “C₁-C₄ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 4 carbon atoms andincludes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

As used herein the term “C₁-C₆ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 6 carbon atoms andincludes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. It will beunderstood that the term “C₁-C₄ alkyl” is included within the definitionof “C₁-C₆ alkyl”.

As used herein the term “C₁-C₁₀ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 10 carbon atoms andincludes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4-methyl-3-heptyl and the like. It will be understood that theterms “C₁-C₄ alkyl” and “C₁-C₆ alkyl” are included within the definitionof “C₁-C₁₀ alkyl”.

As used herein the term “C₁-C₂₀ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 20 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like. It will be understood that theterms “C₁-C₄ alkyl”, “C₁-C₆ alkyl”, and “C₁-C₁₀ alkyl” are includedwithin the definition of “C₁-C₂₀ alkyl”.

As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and “t-Bu” referto methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.

As used herein the term “C₂-C₆ alkenyl” refers to a straight orbranched, monovalent, unsaturated aliphatic chain having from two to sixcarbon atoms. Typical C₂-C₆ alkenyl groups include ethenyl (also knownas vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, andthe like.

As used herein, the term “aryl” refers to monovalent carbocyclic groupcontaining one or more fused or non-fused phenyl rings and includes, forexample, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and the like.

As used herein, the term “C₁-C₆ alkyl-aryl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomswhich has an aryl group attached to the aliphatic chain. Included withinthe term “C₁-C₆ alkyl-aryl” are the following:

and the like.

As used herein the term “(C₃-C₁₀)cycloalkyl” refers to a saturatedhydrocarbon ring structure containing from three to ten carbon atoms.Typical C₃-C₁₀ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. It isunderstood that “(C₃-C₈)cycloalkyl” and “(C₄-C₆)cycloalkyl” is includedwithin the term “(C₃-C₁₀)cycloalkyl”.

As used herein, the term “C₁-C₆ alkyl-(C₃-C₁₀)cycloalkyl” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a (C₃-C₁₀)cycloalkyl attached to the aliphaticchain. Included within the term “C₁-C₆ alkyl-(C₃-C₁₀)cycloalkyl” are thefollowing:

and the like.

As used herein the term “N,N—C₁-C₆ dialkylamine” refers to a nitrogenatom substituted with two straight or branched, monovalent, saturatedaliphatic chains of 1 to 6 carbon atoms. Included within the term“N,N—C₁-C₆ dialkylamine” are —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₂CH₃)₂, and the like.

As used herein the term “C₁-C₆ alkyl-N,N—C₁-C₆ dialkylamine” refers tostraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has an N,N—C₁-C₆ dialkylamine attached to thealiphatic chain. Included within the term “C₁-C₆ alkyl-N,N—C₁-C₆dialkylamine” are the following:

and the like.

As used herein the term “C₁-C₆ alkyl-pyrrolidine” refers to a straightor branched, monovalent, saturated aliphatic chain of 1 to 6 carbonatoms which has a pyrrolidine attached to the aliphatic chain. Includedwithin the scope of the term “C₁-C₆ alkyl-pyrrolidine” are thefollowing:

and the like.

As used herein the term “C₁-C₆ alkyl-piperidine” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomswhich has a piperidine attached to the aliphatic chain. Included withinthe scope of the term “C₁-C₆ alkyl-piperidine” are the following:

and the like.

As used herein the term “C₁-C₆ alkyl-morpholine” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomswhich has a morpholine attached to the aliphatic chain. Included withinthe scope of the term “C₁-C₆ alkyl-morpholine” are the following:

and the like.

The compounds of the present invention contain a tetrazole ring, whichis known to exist as tautomeric structures. The tetrazole, having thedouble bond on the nitrogen atom at the 1-position and the hydrogen onthe nitrogen atom at the 2-position is named as a 2H tetrazole and isrepresented by the following structure.

The corresponding tautomeric form wherein the hydrogen is at thenitrogen atom at the 1-position and the double bond on the nitrogen atomat the 4-position is named as a 1H-tetrazole. The 1H-tetrazole isrepresented by the following formula.

Mixtures of the two tautomers are referred to herein as1(2)H-tetrazoles. The present invention contemplates both tautomericforms as well as the combination of the two tautomers.

The designation “

” refers to a bond that protrudes forward out of the plane of the page.

The designation “

” refers to a bond that protrudes backward out of the plane of the page.

This invention includes the hydrates and the pharmaceutically acceptablesalts of the compounds of formula I. A compound of this invention canpossess a sufficiently basic functional group which can react with anyof a number of inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds of formula I which are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid.Such salts are also known as acid addition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, trifluoroacetic acid, and the like. Examplesof such pharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, trifluoroacetate, propionate, decanoate, caprylate, acrylate,formate, hydrochloride, dihydrochloride, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate,methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, α-hydroxybutyrate,glycolate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and thelike. Preferred pharmaceutically acceptable acid addition salts arethose formed with mineral acids such as hydrochloric acid andhydrobromic acid, and those formed with organic acids such as maleicacid, oxalic acid, triofluoroacetic acid, and methanesulfonic acid.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that such salts may exist as a hydrate.

Examples of salts of the compounds of the present invention include(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 2-ethyl-butyl ester trifluoroacetate salt;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid isobutyl ester trifluoroacetate salt;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 3-methyl butyl ester trifluoroacetate salt;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid decyl ester trifluoroacetate salt; and(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid ethyl ester hydrochloride salt.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation:

${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof formula I can be resolved by one of ordinary skill in the art usingstandard techniques well known in the art, such as those described by J.Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wileyand Sons, Inc., 1981.

The compounds of the present invention have one or more chiral centersand may exist in a variety of stereoisomeric configurations. As aconsequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

The specific stereoisomers and enantiomers of compounds of formula (I)can be prepared by one of ordinary skill in the art utilizing well knowntechniques and processes, such as those disclosed by Eliel and Wilen,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994,Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and byCollet and Wilen, “Enantiomers, Racemates, and Resolutions”, John Wiley& Sons, Inc., 1981. For example, the specific stereoisomers andenantiomers can be prepared by stereospecific syntheses usingenantiomerically and geometrically pure, or enantiomerically orgeometrically enriched starting materials. In addition, the specificstereoisomers and enantiomers can be resolved and recovered bytechniques such as chromatography on chiral stationary phases, enzymaticresolution or fractional recrystallization of addition salts formed byreagents used for that purpose.

The compounds of formula I can be prepared by techniques and proceduresreadily available to one of ordinary skill in the art. Morespecifically, compounds of Formula I can be chemically prepared, forexample, by following the synthetic routes set forth in the Schemebelow. However, the following discussion is not intended to be limitingto the scope of the present invention in any way. For example, thespecific synthetic steps for the route described herein may be combinedin different ways to prepare the compounds of Formula I. Allsubstituents, unless otherwise indicated, are as previously defined. Thereagents and starting materials are readily available to one of ordinaryskill in the art. For example, certain starting materials can beprepared by one of ordinary skill in the art following proceduresdisclosed in U.S. Pat. No. 5,356,902 (issued Oct. 18, 1994) and U.S.Pat. No. 5,446,051 (issued Aug. 29, 1995) and U.S. Pat. No. 5,670,516(issued Sep. 23, 1997) the entire contents, all of which, are hereinincorporated by reference. Other necessary reagents and startingmaterials for the below procedures may be made by procedures which areselected from standard techniques of organic and heterocyclic chemistry,techniques which are analogous to the syntheses of known structurallysimilar compounds, and the procedures described in the Examples,including any novel procedures.

In Scheme I, compound A is esterified to provide the monoester offormula I under standard conditions well known in the art. For example,compound A is dissolved in a suitable organic solvent and treated with asuitable acid, such as hydrochloric acid.

Examples of suitable organic solvents include, methyl alcohol, ethylalcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutylalcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol; hexylalcohol, 3-methylpentyl alcohol, 2-ethylbutyl alcohol, n-heptyl alcohol,n-octyl alcohol, decyl alcohol and the like. The reaction is heated atabout 40° C. to about 60° C. for about 4 hours to about 16 hours. Theproduct is then isolated and purified using techniques well known to oneof ordinary skill in the art, such as extraction techniques andchromatography.

For example, the above reaction is cooled, diluted with a suitableorganic solvent, such as ethyl acetate, washed with saturated sodiumbicarbonate, brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the compound of formula I. Thismaterial may be further purified by flash chromatography on silica gelwith a suitable eluent such as ethyl acetate/hexane.

Alternatively, compound A is dissolved in a suitable organic solvent andtreated with an excess of thionyl chloride. Examples of suitable organicsolvents are anhydrous methyl alcohol, ethyl alcohol, propyl alcohol,isopropyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol,pentyl alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentylalcohol, 2-ethylbutyl alcohol, n-heptyl alcohol, n-octyl alcohol, decylalcohol and the like.

The solution is stirred at reflux for about 1 to 3 hours, and at roomtemperature for about 8 to 16 hr. The mixture is then concentrated undervacuum, and the residue is purified in a manner analogous to theprocedures described above to provide the prodrug monoester of formulaI.

The pharmaceutically acceptable salts of formula I are readily preparedby one of ordinary skill in the art using standard techniques andprocedures. For example, the above product is suspended in diethylether, which has been saturated with HCl gas. The mixture is stirred forabout 1 to 3 hours. The precipitate is then filtered and washed withdiethyl ether under vacuum to provide the pharmaceutically acceptablesalt of the prodrug monoester of formula I.

The following examples represent typical syntheses of the compounds offormula I as described generally above. These examples are illustrativeonly and are not intended to limit the invention in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art. As used herein, the following terms have the meaningsindicated: “eq” or “equiv.” refers to equivalents; “g” refers to grams;“mg” refers to milligrams; “L” refers to liters; “mL” refers tomilliliters; “μL” refers to microliters; “mol” refers to moles; “mmol”refers to millimoles; “psi” refers to pounds per square inch; “min”refers to minutes; “h” refers to hours; “° C.” refers to degreesCelsius; “TLC” refers to thin layer chromatography; “HPLC” refers tohigh performance liquid chromatography; “δ” refers to part per milliondown-field from tetramethylsilane; “THF” refers to tetrahydrofuran;“DMF” refers to N,N-dimethylformamide; “DMSO” refers to methylsulfoxide; “aq” refers to aqueous; “EtOAc” refers to ethyl acetate;“iPrOAc” refers to isopropyl acetate; “MeOH” refers to methanol; “MTBE”refers to tert-butyl methyl ether, and “RT” refers to room temperature.

EXAMPLE 16-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid2-ethyl-butyl ester

To a solution of 2.5 g (8.4 mmol) of6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidmonohydrate (prepared as described in J. Med. Chem., 39 (11), pp.2232-2244, (1996) or U.S. Pat. No. 5,670,516 (issued Sep. 23, 1997)) in20 ml of 2-ethyl-1-butanol, 6.8 ml (92.8 mmol) of thionyl chloride isadded. The solution is stirred at 120° C. for 3 hr. The mixture isconcentrated in vacuo and the residue washed with ethyl ether. Theresidue is purified by SPE (Oasis HLB) to afford the title compound.

Electrospray Mass Spectrum: M+1=364.

EXAMPLE 26-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidisobutyl ester

Prepared according to the procedures essentially as described in Example1, above, using 20 mL of 2-methyl-1-propanol to afford of the titlecompound.

Electrospray Mass Spectrum: M+1=336.

EXAMPLE 36-[2-(2H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid3-methyl-butyl ester

Prepared according to the procedures essentially as described in Example1, above, using using 20 mL of 3-methyl-1-butanol to afford of the titlecompound.

Electrospray Mass Spectrum: M+1=350.

EXAMPLE 46-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic aciddecyl ester

A solution of 2.5 g (8.4 mmol) of6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidmonohydrate in 50 ml decyl alcohol saturated with hydrogen chloride (g)is heated at 120° C. overnight. The mixture is concentrated in vacuo andthe residue purified by SPE (Oasis HLB) to afford the title compound.

Electrospray Mass Spectrum: M+1=420.

EXAMPLE 56-[2-(2H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidethyl ester

A solution of 6.0 g (21.5 mmol) of6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acidmonohydrate in 70 mL of ethanol saturated with hydrogen chloride (g) isheated at reflux overnight. The mixture is concentrated in vacuo,suspended in diethyl ether, and again concentrated in vacuo. The residueis suspended in diethyl ether and heated at reflux for 3 hr. The solidis filtered and rinsed with diethyl ether to afford 7.4 g (100%) of thetitle compound.

Electrospray Mass Spectrum: M+1=308.

Particular Aspects of the Compounds of Formula I:

The following list sets out several groupings of particular substituentsof the compounds of Formula I. It will be understood that the compoundsof Formula I having such particular substituents represent particularaspects of the present invention. It will be further understood thateach of these groupings may be combined with other provided groupings,to create still additional particular aspects of the present invention.

Thus, a particular aspect of the novel compounds of Formula I is onewherein:

-   -   (a) R represents C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkyl-aryl,        C₁-C₆ alkyl-(C₃-C₁₀)cycloalkyl, C₁-C₆ alkyl-N,N—C₁-C₆        dialkylamine, C₁-C₆ alkyl-pyrrolidine, C₁-C₆ alkyl-piperidine,        C₁-C₆ alkyl-morpholine;    -   (b) R represents C₁-C₁₀ alkyl or C₂-C₆ alkenyl;    -   (c) R represents C₁-C₁₀ alkyl or C₁-C₆ alkyl-aryl;    -   (d) R represents C₁-C₁₀ alkyl or C₁-C₆ alkyl-(C₃-C₁₀)cycloalkyl;    -   (e) R represents C₁-C₁₀ alkyl or C₁-C₆ alkyl-N,N—C₁-C₆        dialkylamine;    -   (f) R represents C₁-C₁₀ alkyl or C₁-C₆ alkyl-pyrrolidine;    -   (g) R represents C₁-C₁₀ alkyl or C₁-C₆ alkyl-piperidine;    -   (h) R represents C₁-C₁₀ alkyl or C₁-C₆ alkyl-morpholine;    -   (i) R represents C₁-C₁₀ alkyl;    -   (j) R represents 2-ethyl butyl, isobutyl, 3-methyl butyl, decyl,        or ethyl; or    -   (k) R represents ethyl        Pharmacological Results

The following in vivo data, in rats, dogs and monkeys, exemplify theimprovement in bioavailability of the monoester prodrugs of the presentinvention over the monoacid of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid.

Percent bioavailability is determined using the following equation:

${\frac{{AUC}\mspace{14mu}{p.o.}}{{AUC}\mspace{14mu}{i.v.}} \times \frac{{dose}\mspace{14mu}{i.v.}}{{dose}\mspace{14mu}{p.o.}} \times 100} = {\%\mspace{14mu}{Bioavailability}}$wherein AUC represents the area under the curve, p.o. represents oraldose, and i.v. represents intravenous dose.Bioavailability in Dogs:

Beagle dogs (2 male and 1 female) are administered an oral dose, andlater an iv dose of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (10 mg/Kg p.o; 1 mg/Kg i.v.) to determine oral bioavailability.Subsequently, the same three dogs are administered an oral 10 mg/kg doseof an ester prodrug (for example(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester, HCL salt) to determine whether the prodrug wouldincrease bioavailability of the parent acid. The plasma concentrationsof(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid are determined by LC/MS/MS.

Study Methods:

Live Phase:(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (HCl salt) is dissolved in dilute sodium hydroxide for oraladministration (30 mg/ml) and in 10% ethanol/water for iv administration(10 mg/ml).(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester, HCL salt is dissolved in water for oral administration(30 mg/ml). Dogs weighed between 12 to 15 kg.Results:

The oral bioavailability for3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid was determined to be 18% in dogs. When3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (HCL salt) was administered, bioavailability increasedto 33.1%. The use of the prodrug form3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (HCL salt), provided approximately a 2 fold increase inbioavailability over the parent acid.

Tables 1 below summarizes the pharmacokinetic parameters found forCompounds A and B following 1 mg/kg administration (i.v.) or 10 mg/kgadministration (p.o.) to Beagle Dogs.

TABLE 1 Pharmacokinetic Parameters of Compound A in Beagle Dogs after a1 mg/kg dose of Compound A (i.v.) and a 10 mg/kg dose of Compound A orthe ethyl ester Prodrug, Compound B (p.o.). T_(max) C_(max) AUC %Compound (hr) (ng/mL) (ng hr/mL) Bioavail Improvement A (acid), i.v. —2,820 4,220 — — (1 mg/kg) A (acid), p.o. 4 1,227 7,577 18.0 1 (10 mg/kg)B (ester), p.o. 4 1,662 13,953 33.1 ~2X (10 mg/kg)Bioavailability in Rats

Male Fischer Rats are administered either an oral or iv dose of(3S,4R,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (10 mg/Kg) to determine oral bioavailability. A separate group ofrats are administered an oral 10 mg/kg dose of an ester prodrug (forexample(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester, HCL salt) to determine whether the prodrug wouldincrease bioavailability of the parent acid. The plasma concentrationsof(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid are determined by LC/MS/MS.

Results:

The oral bioavailability for3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid was determined to be 3.6% in rats. When3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (HCL salt) was administered, bioavailability increasedto 17.7%. The use of the prodrug form3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (HCL salt), provided approximately a 5 fold increase inbioavailability over the parent acid.

Tables 2 below summarizes the pharmacokinetic parameters found forCompounds A and B.

TABLE 2 Pharmacokinetic Parameters of Compound A in Fischer Rats after a10 mg/kg Dose of Compound A or the ester Prodrug. Compound B.* T_(max)C_(max) AUC % Compound (hr) (ng/mL) (ng hr/mL) Bioavail Improvement A(acid), i.v. — 11,022 6,727 — A (acid), p.o. 93 241  3.6 1 B (ester),p.o. 265 1,192 17.7 ~5XBioavailability in Cynomolgus Monkeys

Two male and two female monkeys are administered an oral, and later, aniv dose of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (oral: 3 mg/kg; iv: 0.3 mg/kg) to determine oral bioavailability.The same animals are also subsequently administered an oral 3 mg/kg doseof(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester to determine if the ester prodrug form increasesbioavailability of the parent acid. The plasma concentrations of theparent acid are determined by LC/MS/MS.

Study Design

Four cynomolgus monkeys (2/sex) are given a single oral dose of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (3 mg/kg) on day 0, a single iv dose of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (0.3 mg/kg) on day 4 and a single oral dose of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (3 mg/kg) on day 8. Blood samples are collected at 0.5,1, 2, 3, 4, 5, 6 and 8 hours post dose for oral dosing and 0.167, 0.33,0.67, 1, 1.5, 2, 3 and 4 hours post dose for iv dosing. Dosing solutionsfor both the acid and ester are prepared in 0.9% sodium chloride.

Results:

The oral bioavailability for(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid was determined to be 4.5% in monkeys. When(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (HCL salt) was administered, bioavailability increasedto 11.4%. The use of the prodrug form(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester (HCL salt), provided approximately a 2.5 fold increasein bioavailability over the parent acid.

Table 3 below summarizes the pharmacokinetic parameters found forCompounds A and B following i.v. or oral administration to CynomolgusMonkeys.

TABLE 3 Pharmacokinetic Parameters of Compound A in Cynomolgus Monkeysafter an i.v. and p.o. Dose of Compound A or the ester Prodrug, CompoundB. T_(max) C_(max) AUC % Compound (hr) (ng/mL) (ng hr/mL) BioavailImprovement A (acid), i.v. — 1,622 1,076 — (.3 mg/kg) A (acid), p.o. 677 479  4.5 1 (3 mg/kg) B (ester), p.o. 2 301 1225 11.4 ~2.5X (3 mg/kg)

The present invention further provides a method of antagonizing the AMPAor GluR₅ receptors, of the larger class of excitatory amino acidreceptors, which comprises administering to a patient an effectiveamount of a compound of formula I. The excessive or inappropriatestimulation of excitatory amino acid receptors leads to neuronal celldamage or loss by way of a mechanism known as excitotoxicity. Thisprocess has been suggested to mediate neuronal degeneration in a varietyof neurological disorders and conditions. The medical consequences ofsuch neuronal degeneration makes the abatement of these degenerativeneurological processes an important therapeutic goal. For instance,excitatory amino acid receptor excitotoxicity has been implicated in thepathophysiology of numerous neurological disorders, including theetiology of cerebral deficits subsequent to cardiac bypass surgery andgrafting, stroke, cerebral ischemia, spinal cord lesions resulting fromtrauma or inflammation, perinatal hypoxia, cardiac arrest, andhypoglycemic neuronal damage. In addition, excitotoxicity has beenimplicated in chronic neurodegenerative conditions including Alzheimer'sDisease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia,amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson'sDisease, as well as ocular damage and retinopathy. Other neurologicaldisorders implicated with excitotoxicity and/or glutamate dysfunctioninclude muscular spasticity including tremors, drug tolerance andwithdrawal, brain edema, convulsive disorders including epilepsy,depression, anxiety and anxiety related disorders such as post-traumaticstress syndrome, tardive dyslinesia, and psychosis related todepression, schizophrenia, bipolar disorder, mania, and drugintoxication or addiction (see generally U.S. Pat. Nos. 5,446,051 and5,670,516). Excitatory amino acid receptor antagonists may also beuseful as analgesic agents and for treating or preventing various formsof headache, including cluster headache, tension-type headache, andchronic daily headache. In addition, published International Patentapplication WO 98/45720 reports that excitatory amino acid receptorexcitotoxicity participates in the etiology of acute and chronic painstates including severe pain, intractable pain, neuropathic pain,post-traumatic pain.

It is also known that trigeminal ganglia, and their associated nervepathways, are associated with painful sensations of the head and facesuch as headache and, in particular, migraine. Moskowitz (Cephalalgia,12, 5-7, (1992) proposed that unknown triggers stimulate the trigeminalganglia which in turn innervate vasculature within cephalic tissue,giving rise to the release of vasoactive neuropeptides from axonsinnervating the vasculature. These neuropeptides initiate a series ofevents leading to neurogenic inflammation of the meninges, a consequenceof which is pain. This neurogenic inflammation is blocked by sumatriptanat doses similar to those required to treat acute migraine in humans.However, such doses of sumatriptan are associated with contraindicationsas a result of sumatriptan's attendant vasoconstrictive properties. (seeMacIntyre, P. D., et al., British Journal of Clinical Pharmacology, 34,541-546 (1992); Chester, A. H., et al., Cardiovascular Research, 24,932-937 (1990); Conner, H. E., et al., European Journal of Pharmacology,161, 91-94 (1990)). Recently, it has been reported that all five membersof the kainate subtype of ionotropic glutamate receptors are expressedon rat trigeminal ganglion neurons, and in particular, high levels ofGluR₅ and KA2 have been observed. (Sahara et al., The Journal ofNeuroscience, 17(17), 6611 (1997)). As such, migraine presents yetanother neurological disorder which may be implicated with glutamatereceptor excitotoxicity.

The use of a neuroprotective agent, such as an excitatory amino acidreceptor antagonist, is believed to be useful in treating or preventingall of the aforementioned disorders and/or reducing the amount ofneurological damage associated with these disorders. For example,studies have shown that AMPA receptor antagonists are neuroprotective infocal and global ischemia models. The competitive AMPA receptorantagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline)has been reported effective in preventing global and focal ischemicdamage. Sheardown et al., Science, 247, 571 (1900); Buchan et al.,Neuroreport, 2, 473 (1991); LePeillet et al., Brain Research, 571, 115(1992). The noncompetitive AMPA receptor antagonists GKYI 52466 has beenshown to be an effective neuroprotective agent in rat global ischemiamodels. LaPeillet et al., Brain Research, 571, 115 (1992). EuropeanPatent Application Publication No. 590789A1 and U.S. Pat. Nos. 5,446,051and 5,670,516 disclose that certain decahydroisoquinoline derivativecompounds are AMPA receptor antagonists and, as such, are useful in thetreatment of a multitude of disorders conditions, including pain andmigraine headache. WO 98/45270 discloses that certaindecahydroisoquinoline derivative compounds are selective antagonists ofthe iGluR₅ receptor and are useful for the treatment of various types ofpain, including; severe, chronic, intractable, and neuropathic pain.

As such, the compounds of the present invention are believed to beuseful for treating neurological disorders, as discussed above. Suchcompounds could address a long felt need for safe and effectivetreatments for neruological disorders, without attending side effects.Thus, the present invention further provides a method for the treatmentof a neurological disorder, which comprises administering to a patientin need thereof, an effective amount of a compound of formula I. Moreparticularly, the present invention further provides a method for thetreatment of pain or migraine, which comprises administering to apatient in need thereof, an effective amount of a compound of formula I.The treatment of neurological disorders and neurodegenerative diseasesis hereby furthered.

As used herein the term “patient” refers to a mammal, such a mouse,guinea pig, rat, dog, monkey, or human. It is understood that thepreferred patient is a human.

The term “treating” (or “treat”) as used herein includes its generallyaccepted meaning which encompasses prohibiting, preventing, restraining,and slowing, stopping, or reversing progression, severity, of aresultant symptom. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

As used herein the term “effective amount” refers to the amount or doseof the compound, upon single or multiple dose administration to thepatient, which provides the desired effect in the patient underdiagnosis or treatment.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose of compound administered, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

A typical daily dose will contain from about 0.01 mg/kg to about 100mg/kg of the active compound of this invention. Preferably, daily doseswill be about 0.05 mg/kg to about 50 mg/kg, more preferably from about0.1 mg/kg to about 25 mg/kg.

In effecting treatment of a patient afflicted with a condition, diseaseor disorder described above, a compound of formula (I) can beadministered in any form or mode which makes the parent monoacidcompound bioavailable in effective amounts, including oral andparenteral routes. For example, compounds of formula (I) can beadministered orally, subcutaneously, intramuscularly, intravenously,transdermally, intranasally, rectally, buccally, and the like.Alternatively, the compound may be administered by continuous infusion.Oral administration is generally preferred. One skilled in the art ofpreparing formulations can readily select the proper form and mode ofadministration depending upon the particular characteristics of thecompound selected, the disease state to be treated, the stage of thedisease, and other relevant circumstances.

It will be understood by the skilled reader that all of the compoundsused in the present invention are capable of forming salts, and that thesalt forms of pharmaceuticals are commonly used, often because they aremore readily crystallized and purified than are the free bases. In allcases, the use of the pharmaceuticals described above as salts iscontemplated in the description herein, and often is preferred, and thepharmaceutically acceptable salts of all of the compounds are includedin the names of them.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula I or apharmaceutically acceptable salt thereof as defined hereinabove and apharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions are prepared by known procedures usingwell-known and readily available ingredients. In making the compositionsof the present invention, the active ingredient will usually be mixedwith a carrier, or diluted by a carrier, or enclosed within a carrier,and may be in the form of a capsule, sachet, paper, or other container.When the carrier serves as a diluent, it may be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. The compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols, ointments containing, forexample, up to 10% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solutions, and sterilepackaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia,calcium phosphate, alginates, tragcanth, gelatin, calcium silicate,micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 mg to about 500 mg, more preferably about5 mg to about 300 mg (for example 25 mg) of the active ingredient. Theterm “unit dosage form” refers to a physically discrete unit suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. The following formulationexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantify (mg/capsule) Prodrug 250 Starch, dried 200 Magnesium Stearate 10 Total 460

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Tablets each containing 60 mg of active ingredient are made as follows:

Quantity (mg/tablet) Prodrug 60 Starch 45 Microcrystalline Cellulose 35Polyvinylpyrrolidone 4 Sodium Carboxymethyl Starch 4.5 MagnesiumStearate 0.5 Talc 1 Total 150

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

1. A compound of the formula:

wherein R represents C₂-C₁₀ alkyl, or a pharmaceutically acceptable saltthereof.
 2. The compound or salt according to claim 1 wherein Rrepresents 2-ethyl-butyl, isobutyl, 3-methyl-butyl, decyl, or ethyl. 3.The compound or salt according to claim 2 wherein R represents2-ethyl-butyl.
 4. The compound or salt according to claim 2 wherein Rrepresents isobutyl.
 5. The compound or salt according to claim 2wherein R represents 3-methyl-butyl.
 6. The compound or salt accordingto claim 2 wherein R represents decyl.
 7. The compound or salt accordingto claim 2 wherein R represents ethyl.
 8. A salt selected from the groupconsisting of(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 2-ethyl-butyl ester trifluoroacetate salt;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid isobutyl ester trifluoroacetate salt;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 3-methyl butyl ester trifluoroacetate salt;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid decyl ester trifluoroacetate salt; and(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid ethyl ester hydrochloride salt.
 9. A compound which is(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 2-ethyl-butyl ester.
 10. A compound which is(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid isobutyl ester.
 11. A compound which is(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 3-methyl butyl ester.
 12. A compound which is(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid decyl ester.
 13. A compound which is(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid ethyl ester. 14.(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid methyl ester, or a pharmaceutically acceptable salt thereof, inisolated form.
 15. A pharmaceutical composition which comprises acompound of the formula:

wherein R represents C₁-C₁₀ alkyl, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable diluent or carrier.
 16. Thepharmaceutical composition according to claim 15 which comprises(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-isoquinoline-3-carboxylicacid 2-ethyl-butyl ester, or pharmaceutically acceptable salt thereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid isobutyl ester, or pharmaceutically acceptable salt thereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 3-methyl-butyl ester, or a pharmaceutically acceptable saltthereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid decyl ester, or a pharmaceutically acceptable salt thereof; or(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid ethyl ester, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable diluent or carrier.
 17. A method of treatingpain, which comprises administering to a patient an effective amount ofa compound of the formula:

wherein R represents C₁-C₁₀ alkyl, or a pharmaceutically acceptable saltthereof.
 18. The method according to claim 17, which comprisesadministering to a patient an effective amount of(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 2-ethyl-butyl ester, or pharmaceutically acceptable salt thereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid isobutyl ester, or pharmaceutically acceptable salt thereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 3-methyl-butyl ester, or a pharmaceutically acceptable saltthereof; (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid decyl ester, or a pharmaceutically acceptable salt thereof; or(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid ethyl ester, or a pharmaceutically acceptable salt thereof.
 19. Amethod of treating migraine, which comprises administering to a patientan effective amount of a compound of the formula:

wherein R represents C₁-C₁₀ alkyl, or a pharmaceutically acceptable saltthereof.
 20. The method according to claim 19, which comprisesadministering to a patient an effective amount of(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 2-ethyl-butyl ester, or pharmaceutically acceptable salt thereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid isobutyl ester, or pharmaceutically acceptable salt thereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid 3-methyl-butyl ester, or a pharmaceutically acceptable saltthereof;(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid decyl ester, or a pharmaceutically acceptable salt thereof; or(3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylicacid ethyl ester, or a pharmaceutically acceptable salt thereof.